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Animals
Animals, Newborn
Apoptosis Inducing Factor/metabolism
Brain/cytology
Caspase 9/metabolism
Cell Differentiation/drug effects/*physiology
Cell Survival/drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Electron Transport Complex IV/drug effects/*metabolism
Enzyme Inhibitors/pharmacology
In Situ Nick-End Labeling/methods
Membrane Potential, Mitochondrial/drug effects/physiology
Mitochondria/drug effects/*metabolism
Neuroglia/drug effects/physiology
Oligodendroglia/drug effects/*physiology/*ultrastructure
Rats
Reactive Oxygen Species/metabolism
Sodium Azide/pharmacology
Spectrophotometry/methods
Stem Cells/drug effects/physiology
Time Factors
Abstract:
Oligodendrocyte lineage cells are susceptible to a variety of insults including hypoxia, excitotoxicity, and reactive oxygen species. Demyelination is a well-recognized feature of several CNS disorders including multiple sclerosis, white matter strokes, progressive multifocal leukoencephalopathy, and disorders due to mitochondrial DNA mutations. Although mitochondria have been implicated in the demise of oligodendrocyte lineage cells, the consequences of mitochondrial respiratory chain defects have not been examined. We determine the in vitro impact of established inhibitors of mitochondrial respiratory chain complex IV or cytochrome c oxidase on oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes as well as on differentiation capacity of OPCs from P0 rat. Injury to mature oligodendrocytes following complex IV inhibition was significantly greater than to OPCs, judged by cell detachment and mitochondrial membrane potential (MMP) changes, although viability of cells that remained attached was not compromised. Active mitochondria were abundant in processes of differentiated oligodendrocytes and MMP was significantly greater in differentiated oligodendrocytes than OPCs. MMP dissipated following complex IV inhibition in oligodendrocytes. Furthermore, complex IV inhibition impaired process formation within oligodendrocyte lineage cells. Injury to and impaired process formation of oligodendrocytes following complex IV inhibition has potentially important implications for the pathogenesis and repair of CNS myelin disorders.
